Studies of the mechanisms by which SIV live attenuated vaccines provide robust protection have the potential to facilitate design of vaccines to prevent HIV infection. We recently discovered in the SIV-rhesus macaque model of HIV-1 transmission to women that mucosal antibodies to oligomeric gp41 are the principal correlate of the local protection against vaginal challenge conferred by live attenuated SIVmac239nef vaccination. We propose to investigate strategies to reproduce these protective effects by passive immunization with gp41 antibodies, and by immunization with recombinant gp41 immunogens that target Ab to the neonatal Fc- receptor positive cervical and vaginal epithelium. We will test the hypothesis that antibodies concentrated at the portals of entry in the female reproductive tract will be able to intercept virus during early phases of viral replication and spread and thereby protect against systemic infection. Our primary focus will therefore be to analyze the location of antibodies and associated decrease in viral replication in cervical tissues in the critical first 7 days following vaginal exposure, when the vulnerable founder population of infected cells must be established and expand locally for a robust systemic infection to ensue. Our Specific aims are 1) to assess protective effects of passive immunization with a rhesus monoclonal antibody with similar reactivity to tissue antibodies to oligomeric gp41 induced by SIVmac239nef vaccination; and 2) to determine the location and local protective effects of antibodies elicited by a recombinant oligomeric gp41 to compare with previous results obtained in studies of SIVmac239nef vaccination. Insights from these studies hold promise for understanding how to generate and focus an antibody response at the portal of entry at a time when it has the most favorable opportunity to prevent and contain infection. PUBLIC HEALTH RELEVANCE: An effective HIV-1 vaccine is urgently needed, particularly to prevent transmission to women who increasingly bear the brunt of newly acquired infections. The proposed research is based on a protective live attenuated vaccine, and seeks to reproduce these protective effects without the associated safety issues, with novel immunogens and strategies that focus the immune response on intercepting infection at the portal of entry in its early stages of infection when virus is most vulnerable.